Diabetes Mellitus, Type 2Phase 3NCT03508739
Glucagon-like Peptide-1 Metabolism and Acute Neprilysin Inhibition
A Phase 3 study testing Sacubitril/Valsartan 200mg (blinded) and Valsartan 160mg (blinded) in people with Diabetes Mellitus, Type 2 and Pre-diabetic, run by University of Pennsylvania at 1 site in United States.
Trial summary
Type 2 diabetes is common, increases in prevalence with age, and patients with diabetes have an increased risk of cardiovascular disease. A relatively new cardiovascular medication currently used for the treatment of heart failure in the United States inhibits an enzyme that breaks down a variety of signaling… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Diabetes Mellitus, Type 2, Pre-diabetic, Hypertension
- What is being tested?
- Sacubitril/Valsartan 200mg (blinded) and Valsartan 160mg (blinded)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2018to 30 Jun 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women ages 18-80 years
- Type 2 diabetes mellitus (T2DM) or pre-diabetes, controlled by diet alone or metformin therapy and elevated blood pressure
- Pre-diabetes is defined as fasting plasma glucose of 100-125 mg/dL, plasma glucose of 140-199 mg/dL two hours after 75g oral glucose load, or hemoglobin A1C 5.7-6.4%. T2DM is defined as fasting plasma glucose of ≥126 mg/dL, plasma glucose of ≥200 mg/dL two hours after 75g oral glucose load, or hemoglobin A1C ≥6.5%.
- Elevated blood pressure is defined as systolic blood pressure (BP) ≥130 mmHg or diastolic BP ≥80 mmHg on three occasions or therapy with antihypertensive medication(s) for a minimum of three months.
- For female subjects, the following conditions must be met:
- Postmenopausal status for at least one year or
- Status post-surgical sterilization, or
- If childbearing potential, utilization of birth control (barrier methods, abstinence, hormonal contraception, etc) and willingness to undergo regular beta hCG monitoring prior to drug treatment and on each study day. (Valsartan is pregnancy category D.)
Who cannot join
- Type 1 diabetes
- Poorly controlled T2DM, defined as hemoglobin A1C ≥8.7%
- Use of anti-diabetic medications other than metformin for over 24 months prior to initiation of the study.
- Requiring the need for insulin therapy
- Secondary hypertension
- Severe hypertension requiring the use of more than two anti-hypertensive agents other than a stable dose of diuretic or blood pressure > 180/110 mmHg
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- Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months
- Pregnancy or breastfeeding
- History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, angiotensin converting enzyme inhibitors, ARBs, or NEP inhibitors, as well as known or suspected contraindications to the study drugs
- History of angioedema
- History of pancreatitis or known pancreatic lesions
- Clinically significant gastrointestinal impairment that could interfere with drug absorption
- Significant cardiovascular disease such as myocardial infarction or cardiovascular surgery or angioplasty within six months prior to enrollment, presence of angina pectoris, arrhythmia with history of or risk of syncopal episodes or need for antiarrhythmic therapy, congestive heart failure (LV hypertrophy and diastolic dysfunction acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, hypertrophic cardiomyopathy, or coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
- Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3 x upper limit of normal range)
- Impaired renal function (eGFR< 50mL/min/1.73m2 as determined by the MDRD equation)
- History or presence of immunological or hematological disorders
- Serum potassium >5.2 mmol/L at screening
- History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
- Hematocrit <35%
- Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
- Clinically significant gastrointestinal impairment that could interfere with drug absorption
- Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with daily use of non-steroidal anti-inflammatory drugs
- Treatment with chronic systemic glucocorticoid therapy within the last year
- Treatment with systemic glucocorticoid therapy acutely within six weeks prior to enrollment
- Treatment with lithium salts
- History of alcohol or drug abuse
- Treatment with anticoagulation
- Treatment with any investigational drug in the one month preceding the study
- Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
- Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
Official title: Glucagon-like Peptide-1 Metabolism in the Setting of Acute Neprilysin Inhibition
Type 2 diabetes is common, increases in prevalence with age, and patients with diabetes have an increased risk of cardiovascular disease. A relatively new cardiovascular medication currently used for the treatment of heart failure in the United States inhibits an enzyme that breaks down a variety of signaling hormones. This clinical trial tests if it may also be a target for the treatment of diabetes by decreasing the breakdown of a hormone that increases insulin release after a meal.
Read the detailed description
This study will test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous glucagon-like peptide-1 (GLP-1) after a mixed meal compared to valsartan. The primary statistical analysis will be within subject comparison (paired t-test or nonparametric equivalent) of area under the curve intact GLP-1 after the meal during sacubitril/valsartan compared to valsartan. Neprilysin inhibition may be a new drug target for the treatment of type 2 diabetes by increasing intact GLP-1 and may be of particular benefit to individuals with increased risk of hypoglycemia and cardiovascular disease.
- Being tested
- Sacubitril/Valsartan 200mg (blinded), Valsartan 160mg (blinded)
- Medical subject headings
- Diabetes Mellitus, Type 2, Glucose Intolerance, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sacubitril/Valsartan 200mg (blinded)Drug
Also called Entresto
study day 2 for AB and study day 3 for BA
Valsartan 160mg (blinded)Drug
Also called Diovan
study day 3 for AB and study day 2 for BA
| Study group | Role | What they receive |
|---|---|---|
| ARM 1: randomization order AB | Experimental | Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order AB). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. Receives: Drug: Sacubitril/Valsartan 200mg (blinded); Drug: Valsartan 160mg (blinded) |
| ARM 2: randomization order BA | Experimental | Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order BA). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. Receives: Drug: Sacubitril/Valsartan 200mg (blinded); Drug: Valsartan 160mg (blinded) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal
GLP-1 is a hormone released after a meal that has been shown to improve insulin and glucose dynamics. It is a target for diabetes therapies. We will compare GLP-1 levels during the different drug treatments and at baseline.
Measured: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Secondary outcomes (4)
Insulin levels after the mixed meal
Insulin is a hormone released from the pancreas that helps with blood glucose control. We will measure insulin levels during the different drug treatments and at baseline.
Measured: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Blood glucose levels after the mixed meal
We will compare blood glucose levels during the different drug treatments and at baseline.
Measured: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Triglyceride levels after the mixed meal
Triglycerides are a component of a routine lipid/ cholesterol panel. They rise in the setting of increased fat intake. GLP-1 is thought to decrease triglyceride levels. We will compare triglyceride levels during the different drug treatments and at baseline.
Measured: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Neprilysin enzyme (drug) activity at baseline, during sacubitril/valsartan, and during valsartan
Neprilysin is an enzyme that breaks down several proteins, including glucagon-like peptide-1 (GLP-1). Sacubitril in sacubitril/valsartan is a pro-drug of a neprilysin inhibitor. This assay level will help to determine if the changes seen after the meal are related to alterations in this enzyme activity and administration of the drug sacubitril/valsartan compared to valsartan. We will measure this before the medication is administered (thus at baseline) and two hours after the drug is administered and just prior to the mixed meal.
Measured: Time points -120 min (before drug given) and 0 min (2 hours after drug dose, just prior to the meal)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2018
- Study start1 Jun 2018
- Primary completion30 Jun 2026
- Study completion30 Jun 2026
Why it stopped: We do not have active funding.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- prospective randomized, double-blind, crossover study, mechanistic/ translational study (not to change labeling or marketing, not classic phase 3 or 4 study), IND exempt
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jessica R.Wilson, MD, MS, University of Pennsylvania
- Investigators
- Jessica R Wilson, MD, MSCI, Principal investigator, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03508739
- Sponsor's protocol ID
- 828731
- Status last verified
- Sep 2026
- First submitted
- 7 Nov 2017
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: This study will not have large scale genomic data to share. The maximum number of participants will be 50.
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Glucagon-like Peptide-1 Metabolism in the Setting of Acute Neprilysin Inhibition
- ClinicalTrials.gov ID
- NCT03508739
- Acronym / sponsor ID
- 828731
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: We do not have active funding.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 30 Jun 2026 (actual)
- Study completion
- 30 Jun 2026 (actual)
- First posted
- 26 Apr 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Type 2 diabetes is common, increases in prevalence with age, and patients with diabetes have an increased risk of cardiovascular disease. A relatively new cardiovascular medication currently used for the treatment of heart failure in the United States inhibits an enzyme that breaks down a variety of signaling hormones. This clinical trial tests if it may also be a target for the treatment of diabetes by decreasing the breakdown of a hormone that increases insulin release after a meal.
Detailed description
This study will test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous glucagon-like peptide-1 (GLP-1) after a mixed meal compared to valsartan. The primary statistical analysis will be within subject comparison (paired t-test or nonparametric equivalent) of area under the curve intact GLP-1 after the meal during sacubitril/valsartan compared to valsartan. Neprilysin inhibition may be a new drug target for the treatment of type 2 diabetes by increasing intact GLP-1 and may be of particular benefit to individuals with increased risk of hypoglycemia and cardiovascular disease.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- prospective randomized, double-blind, crossover study, mechanistic/ translational study (not to change labeling or marketing, not classic phase 3 or 4 study), IND exempt
| Arm | Type | Receives |
|---|---|---|
| ARM 1: randomization order AB | Experimental | Drug: Sacubitril/Valsartan 200mg (blinded), Drug: Valsartan 160mg (blinded)Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order AB). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. |
| ARM 2: randomization order BA | Experimental | Drug: Sacubitril/Valsartan 200mg (blinded), Drug: Valsartan 160mg (blinded)Subjects will present for a baseline mixed meal study day 1 (no medication). Next they will be randomized to sacubitril/valsartan 200mg po and then valsartan 160 mg po with each medication given on study day 2 and 3, respectively (order BA). At each study day, subjects will present after fasting and receive blinded study medication on study days 2 and 3. After an IV is placed, neprilysin activity will be measured at baseline. Two hours later, subjects will have neprilysin activity collected again as well as baseline insulin, glucose, GLP-1, and triglycerides. Following this, subjects will ingest a mixed meal. Blood samples for insulin, glucose, GLP-1, and triglycerides will be collected after the meal for four hours total. Blood pressure and heart rate will be monitored. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Men and women ages 18-80 years
- Type 2 diabetes mellitus (T2DM) or pre-diabetes, controlled by diet alone or metformin therapy and elevated blood pressure
- For female subjects, the following conditions must be met:
Key exclusion criteria (30 listed)
- Type 1 diabetes
- Poorly controlled T2DM, defined as hemoglobin A1C ≥8.7%
- Use of anti-diabetic medications other than metformin for over 24 months prior to initiation of the study.
- Requiring the need for insulin therapy
- Secondary hypertension
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sacubitril/Valsartan 200mg (blinded)Also: Entrestostudy day 2 for AB and study day 3 for BA | Drug | ARM 1: randomization order AB, ARM 2: randomization order BA |
| Valsartan 160mg (blinded)Also: Diovanstudy day 3 for AB and study day 2 for BA | Drug | ARM 1: randomization order AB, ARM 2: randomization order BA |
Primary outcome
Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal
Time frame: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
GLP-1 is a hormone released after a meal that has been shown to improve insulin and glucose dynamics. It is a target for diabetes therapies. We will compare GLP-1 levels during the different drug treatments and at baseline.
4 secondary outcomes
Insulin levels after the mixed meal
Time frame: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Blood glucose levels after the mixed meal
Time frame: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Triglyceride levels after the mixed meal
Time frame: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)
Neprilysin enzyme (drug) activity at baseline, during sacubitril/valsartan, and during valsartan
Time frame: Time points -120 min (before drug given) and 0 min (2 hours after drug dose, just prior to the meal)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
- Individual participant dataSharing planned: No. This study will not have large scale genomic data to share. The maximum number of participants will be 50.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jessica R Wilson, MD, MSCI principal investigator
University of Pennsylvania
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Sacubitril/Valsartan 200mg (blinded) and Valsartan 160mg (blinded) in people with Diabetes Mellitus, Type 2 and Pre-diabetic, run by University of Pennsylvania at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Intact glucagon like peptide-1 (GLP-1) levels after the mixed meal (time frame: This will be measured just before the meal and after the meal at pre-specified time points for a total of four hours. (Time points 0 to 4 hours)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.